Exploring the Cardiotoxicity Spectrum of Anti-Cancer Treatments: Definition, Classification, and Diagnostic Pathways

Early detection and treatment of cancer have led to a noticeable reduction in both mortality and morbidity. However, chemotherapy and radiotherapy could exert cardiovascular (CV) side effects, impacting survival and quality of life, independent of the oncologic prognosis. In this regard, a high clinical index of suspicion is required by the multidisciplinary care team in order to trigger specific laboratory tests (namely natriuretic peptides and high-sensitivity cardiac troponin) and appropriate imaging techniques (transthoracic echocardiography along with cardiac magnetic resonance, cardiac computed tomography, and nuclear testing (if clinically indicated)), leading to timely diagnosis. In the near future, we do expect a more tailored approach to patient care within the respective community along with the widespread implementation of digital health tools.


Introduction
Early detection and treatment of cancer have led to a noticeable reduction in both morbidity and mortality of malignancies [1]. However, conventional chemotherapeutics and some of the newer anti-cancer signaling inhibitors (e.g., antibodies and protein kinase inhibitors or immune checkpoint inhibitors (ICI)) could exert cardiovascular (CV) side effects impacting the patient's survival and quality of life, independent of the oncologic prognosis [2,3].

Introduction
Early detection and treatment of cancer have led to a noticeable reduction in both morbidity and mortality of malignancies [1]. However, conventional chemotherapeutics and some of the newer anti-cancer signaling inhibitors (e.g., antibodies and protein kinase inhibitors or immune checkpoint inhibitors (ICI)) could exert cardiovascular (CV) side ef fects impacting the patient's survival and quality of life, independent of the oncologic prognosis [2,3].
In this regard, several scientific associations of cardiologists and oncologists have made an effort to better define the management of adverse sequelae of cancer therapy related cardiovascular toxicity (CTR-CVT), leading to a new discipline known as cardio oncology [4][5][6] (Figures 1 and 2). Therefore, the aim of this paper is to discuss the full spectrum of CTR-CVT and related diagnosis through a pragmatic approach mainly based on pre-existing guidelines. An integrated multidisciplinary approach in management of cancer patients [7]. Therefore, the aim of this paper is to discuss the full spectrum of CTR-CVT and related diagnosis through a pragmatic approach mainly based on pre-existing guidelines.

Cancer Therapy Related Cardiac Dysfunction
CTRCD is classified into two main clinical categories: (i) Asymptomatic CTRCD (mild: left ventricular ejection fraction (LVEF) ≥50% accompanied by a relative decline in global longitudinal strain (GLS) of >15% from baseline and/or a new increase in cardiac biomarkers; moderate: new LVEF reduction ≥10% to an LVEF of 40-49% or new LVEF reduction <10% to an LVEF of 40-49% and an either new relative decline in GLS of >15% from baseline or a new increase in cardiac biomarkers; severe: new LVEF reduction to <40%); (ii) Symptomatic CTRCD (overt heart failure (HF), ranging from mild to very severe)) [7]. Of note, the InterTAK Registry investigators have reported a higher rate of Takotsubo syndrome (TTS) in cancer patients compared with the general population as a consequence of cancer treatments toxicity (e.g., 5-fluorouracil (5-FU), ICI, vascular endothelial growth factor inhibitors (VEGFi) and tyrosine kinase inhibitors (TKIs)) along with increased emotional stress and elevated sympathetic tone [8].
Specific CTRCD a.
Anthracyclines (e.g., doxorubicin, epirubicine, daunorubicin) are frequently employed treatment of solid tumors and hematological tumors but could contribute to the development of left ventricular dysfunction (LVD) (from myocardial cell injury to impaired LVEF and symptomatic HF) [9]. The proposed mechanisms of anthracycline-related cardiomyopathy include the transport of anthracyclines across the cardiomyocyte cell membrane, generation of reactive oxygen species (ROS) through the inhibition of topoisomerase 2β (resulting in activation of cell death pathways and mitochondrial dysfunction), generation of cardiotoxic anthracycline metabolites, and sarcomere disruption [2,10]. b.
Alkylating agents, such as cyclophosphamide, given in high doses before bone marrow transplantation, may cause HF due to several pathological effects as direct endothelial injury followed by extravasation of toxic metabolites that damage myocytes, interstitial hemorrhage, and edema. Furthermore, an ischemic myocardial injury could be the result of intracapillary microemboli. Cyclophosphamide may also damage the inner mitochondrial membrane of cardiomyocytes, most likely through the induction of oxidative stress [11]. c.
Cardiotoxicity of cisplatin, used for solid cancers (e.g., testicular, lung, cervical, and ovarian cancers), may result either from direct toxic action on cardiac myocytes or from ROS production, followed by the induction of oxidative stress and the switch to a prothrombotic condition [12]. Of note, platinum-based drugs need an infusion of high intravenous volumes to avoid cardio-toxicity [2,11]. d.
Immunotherapies and targeted therapies-implying inhibition of human epidermal growth factor receptor 2 (HER2) signaling with either antibodies (trastuzumab, pertuzumab) or TKIs (lapatinib)-have ameliorated survival of patients with HER2positive breast cancer [2,13]. In addition, 3% to 7% of patients who receive trastuzumab monotherapy develop cardiac dysfunction (from asymptomatic LVEF decline to HF), which is usually reversible with drug interruption and/or HF treatment [2]. This percentage is even higher when trastuzumab is administrated after anthracyclines treatment [2]. e.
Both antibodies and protein kinase vascular endothelial growth factor (VEGF) signaling pathway inhibitors, used in several solid cancers (e.g., colorectal and lung cancer), induce LVD and HF mainly due to cardiac hypertrophy and mitochondrial abnormalities [2]. In particular, sorafenib-mediated inhibition of RAF1 and BRAF kinase activity will disrupt signaling through the extracellular signal-regulated kinase (ERK) kinase cascade, which is believed to have a role in heart cell survival, especially under conditions of stress [2]. f.
HF due to TKIs of BCR-ABL (e.g., imatinib, employed in chronic leukemia) has not been uniquely confirmed. However, these drugs could lead to significant mitochondrial dysfunction with loss of membrane potential, the release of cytochrome c, and markedly impaired energy generation with a significant decline in adenosine triphosphate (ATP) concentration, which is crucial to cardiomyocyte contractile function [2].
g. Antimicrotubule agents (taxanes, such as docetaxel), frequently used in breast cancer, may be safer than anthracyclines in patients with pre-existing LVD. However, asymptomatic decrease in LVEF as well as overt congestive HF have been observed in patients previously treated with anthracycline and when docetaxel was combined with trastuzumab treatment for HER2-positive disease [2,11,14]. h.
Several investigators have demonstrated LVD related to proteasome inhibitors (PI), used in multiple myeloma, as a direct consequence of the inability of proteasomes to degrade dysfunctional or unneeded proteins in cardiomyocytes [2]. i.
ICIs may cause (through not entirely known mechanisms of action) myocarditis as well as non-inflammatory HF syndromes including Takotsubo syndrome [7]. j.
Chimeric antigen receptor T cell (CAR-T) therapies can be associated with clinically silent elevation in cardiac troponins (cTn) to decompensated HF [7,15]. k.
In addition to chemotherapy, radiation-induced CVD (increased risk for systolic and diastolic (more likely) heart failure) may be observed [16]. The related pathophysiological mechanisms are complex, including deoxyribonucleic acid damage, oxidative stress, and the release of inflammatory and profibrotic cytokines, leading to vascular and myocardial fibrosis, and as a result, the development of stenosis in radiated coronary arteries, subclavian, and carotids [2,16].

Myocarditis
Myocarditis is usually associated with ICI, which has recently been implemented to treat resistant malignancies [17,18]. The diagnosis of ICIs myocarditis includes cTn elevation along with diagnostic cardiac magnetic resonance (CMR)-specific markers based on updated Lake Louise criteria after exclusion of acute coronary syndromes (ACS) and (although rare) acute infectious etiology [7]. Endomyocardial biopsy is indicated in the case of an ongoing unstable hemodynamic state or uncertain diagnosis [19].

Vascular Toxicity
Vascular chemotherapeutic agents' toxicities include a broad spectrum of cardiovascular manifestations, both asymptomatic (atherosclerosis and abnormal vasoreactivity) and symptomatic (stroke/transient ischemic attack, myocardial infarction, ACS and chronic coronary syndromes, peripheral artery disease (PAD), vasospastic and microvascular angina, and Raynaud's phenomenon).

Coronary Artery Disease (CAD)
Mechanisms of coronary artery toxicity consist (and may coexist) in direct vasospastic effect (fluoropyrimidines), endothelial injury (fluoropyrimidines, Veggie, radiotherapy), acute arterial thrombosis (cisplatin), vasculitis (ICI), and long-term changes of lipid metabolism with resulting early arteriosclerosis (ALK inhibitors, BCR-ABL TKIs) [2]. There is also evidence that previous radiotherapy of mediastinum may cause or accelerate drugrelated coronary disease as it provokes endothelial injury and plaque rupture, and favors thrombosis with a risk proportional to irradiation dose [2,16].

Peripheral Vascular Disease and Stroke
Severe atherosclerotic and non-atherosclerotic PAD in the lower extremities can occur in patients (up to 30%) treated with nilotinib, ponatinib, or BCR-ABL TKIs (used for chronic myeloid leukemia). TKIs can induce a vasospasm on stenosis in arteries and exert proatherogenic effects on endothelial cells [20]. Bleomycin, cyclophosphamide, vinka alcaloids, cisplatin, methotrexate, 5-FU, and paclitaxel could cause peripheral arterial toxicities such as Raynoud's phenomenon and ischemic stroke [21].
After mediastinal, cervical, or cranial radiotherapy, the risk of stroke is doubled [22]. The proposed mechanisms, on one hand, are endothelial damage and thrombus formation in small vessels and, on the other hand, vasa vasorum occlusions, necrosis/fibrosis, and accelerated atherosclerosis of the medium or large vessels (including carotid, aorta, subclavian, and iliofemoral) [2].

Thromboembolic Disease
In addition to cancer itself and the patient's risk profile, venous thromboembolism (VTE) can be directly related to chemotherapy and its administration route (use of indwelling venous catheters) [23]. In this regard, it should be noted that VTE is among the most frequent causes of death after cancer surgery [2]. Recommendations for both prophylaxis and treatment of VTE in patients with cancer and COVID-19 are similar to those of patients without COVID-19 [24,25]. As a note, intra-arterial thrombotic events may also but rarely occur in cancer patients under anthracyclines, taxanes, and platinum-based chemotherapies [2,26].
Other chemotherapeutics (BCR-ABL TKI, brigatinib, ibrutinib, fluoropyrimidines, cisplatin, enzalutamide) could also provoke HTN, which is also often fostered by the use of corticosteroids and non-steroidal anti-inflammatory drugs along with factors as stress and pain [7].

Arrhythmias
Both tachyarrhythmia and bradyarrhythmia may be related to cancer-related therapy [2,30]. Atrial fibrillation (AF) is the most frequent chemotherapy (alkylating agents, anthracyclines, antimetabolites, etc.) and/or radiotherapy-related supraventricular tachyarrhythmia. [31]. It may also be commonly observed after cancer surgery. However, most cancer patients present several AF predisposing factors (advanced age, electrolyte abnormalities, hypoxia, metabolic disorders, etc.) that need to be considered by the treating multidisciplinary team during the clinical evaluation.
QT prolongation (most frequently caused by arsenic trioxide) and ventricular arrhythmias are usually related to several chemotherapeutics (alkylating agents, amsacrine, antimetabolites, arsenic trioxide, doxorubicin, etc.) as well as radiotherapy should also be taken into account when treating cancer patients [2].
Less frequently, chemotherapy can cause sinus node dysfunction leading to bradycardia, and heart blocks [2,32]. As a note, conduction defects may also appear after many years after neck radiotherapy directly linked to autonomic dysfunction secondary to injury and fibrosis of the carotid sinus [16].

Pericardial Disease
Acute pericarditis (with/without large effusion leading to hemodynamic instability such as tamponade) may be observed with the use of several chemotherapeutic drugs (predominantly anthracyclines, cyclophosphamide, cytarabine, bleomycin, ICI) and/or after high dose radiotherapy as in the case of mediastinal tumors [2,33,34]. Furthermore, chronic constrictive pericarditis may rarely occur several years later in high-dose radiotherapy [2,16,35].

Valvular Heart Disease
Chemotherapeutic agents do not directly target cardiac valves, but in cancer patients VHD may be detected as secondary to ventricular dysfunction (mitral and/or tricuspid regurgitation) and/or endocarditis (bacteremia and sepsis due to chemotherapy-associated pancytopenia and/or indwelling catheters) [4,[36][37][38]. Radiation-induced VHD has been also reported among~10% of treated patients [2,39]. It should be noted that left-sided valves are more commonly affected, with the aortic valve being the most involved one [35,40].
Cancer therapy related-VHD is usually characterized by an unusual pattern of calcification extending from the base of the anterior mitral leaflet to the noncoronary aortic sinus [41]. Calcification typically spares the tips of mitral valve leaflets and does not lead to commissural fusion [16].

Pulmonary Hypertension
PH is a rare but serious complication of anti-cancer treatments and stem cell bone marrow transplantation [7,42]. In this regard, dasatinib (used for chronic myelogenous leukemia) can generate serious precapillary PH (through smooth muscle cell proliferation in pulmonary arterioles and vasoconstriction (group 1)) that is usually reversible after drug cessation and consequent relative change with another TKI, such as nilotinib [43]. Furthermore, severe pulmonary veno-occlusive disease (group 1) has been reported among cancer patients treated with cyclophosphamide and other alkylating agents. PH may be also related to CTRCD (group 2), pulmonary fibrosis (secondary to thoracic radiation or bleomycin) (group 3), central venous catheter and/or malignant tumors (e.g., renal carcinoma) (group 4), or multifactorial mechanisms (group 5) [7].

Diagnostic Pathways
Cardiotoxicity diagnosis relies on timely high clinical suspicion (anamnesis, physical examination, and electrocardiogram) triggering specific serum biomarkers (namely natriuretic peptides (NPs) and cTn) and appropriate imaging techniques (transthoracic echocardiography (TTE) along with CMR, cardiac computed tomography (CCT) and nuclear testing (if clinically indicated)).

Clinical Assessment
A careful baseline clinical assessment (anamnesis, physical examination, and electrocardiogram) is recommended in all patients starting cancer treatment to estimate the personal risk of developing CTR-CVT. According to current 2022 ESC guidelines on cardiooncology [7], the baseline risk assessment should be easily pursued through drug relatedproformas provided by the Heart Failure Association-International Cardio-Oncology Society (HFA-ICOS) for all patients who are expected to receive potentially cardiotoxic cancer therapy [7]. In this regard, cancer patients are divided into four CTR-CVT baseline risk categories (low, moderate, high, and very high) and in turn, referred to the specific related surveillance program [7].

Serum Biomarkers
Amongst serum biomarkers validated in the detection of cardiotoxicity, NPs and cTn are the most used in daily clinical practice [44,45].
NPs, including B-type natriuretic peptide (BNP) and N-terminal pro-B-type natriuretic peptide (NT-proBNP), are quantitative and qualitative markers for the presence and severity of hemodynamic cardiac stress as in HF [46].
Short-term temporal changes in high-sensitivity cardiac troponin (hs-cTn) concentrations can differentiate acute disease (rapid rise and/or fall) from chronic cardiomyocyte injury (persistent slight elevation) [47]. As noted, chronic cTn elevation can be associated with the presence of comorbidities such as chronic kidney disease, diabetes mellitus, significant left ventricular hypertrophy, and HF [48].
According to Lyon et al. and based on our experience, serial NPs and hs-cTn measurements should be undertaken in all patients with cancer at risk of CTRCD [7,44].
Several novel biomarkers (e.g., myeloperoxidase, high-sensitivity C-reactive protein, sFlt-1, placental growth factor, growth differentiation factor-15, galectin-3, arginine, hearttype of fatty acid binding protein, glycogen phosphorylase BB) have been studied to detect earlier or subclinical cardiotoxicity and institute cardioprotective strategies beyond the prediction currently offered by cTn and NPs [49,50]. In addition, markers of the immune system, (i.e., immunoglobulin E), could help to identify patients at increased risk for doxorubicin and trastuzumab cardiotoxicity [51]. Lastly, recent studies in breast cancer patients have indicated microRNAs as a potential biomarker in the detection of cancer drug-induced cardiotoxicity [52], as shown in (Table 2) [51,53-60].

Transthoracic Echocardiography
TTE (non-invasive, radiation-free, and virtually implementable in any clinical scenario) is recommended as the first-line imaging modality in cancer patients (Figure 3).
In addition, it provides accurate information regarding heart structure, function, and derived Doppler intracardiac hemodynamics (Table 3). In addition, it provides accurate information regarding heart structure, function, and derived Doppler intracardiac hemodynamics (Table 3). Table 3. Echocardiography protocol for cardio-oncology surveillance [33,38,61].

LVEF by Simpson's 2D, or (semi)automatic 3D
Drop >10% (percentage points) for 2D, >5% for 3D from pre-treatment value 2D/3D GLS, GCS Relative reduction by >10-15% from pre-treatment value and to below lower limit of normal LV 2D/3D systolic and diastolic volumes Increase by 15    It should be emphasized that advanced ultrasound techniques (namely strain and 3dimensional echocardiography) may provide new insights into the evaluation of chemotherapy and/or radiotherapy CV side effects. In this regard, GLS has emerged as a new marker of early subclinical ventricular dysfunction not usually detected by conventional two-dimensional parameters such as LVEF [62]. Therefore, if available, a strain imaging technique is recommended every time an echocardiographic exam is performed [7].

Transephofageal Echocardiography (TEE)
TEE, performed by TEE-experienced physicians, gives key information concerning the diagnosis of infective endocarditis, acute aortic syndromes, intracardiac shunts, cardiac (suspected tumor or thrombus), and pericardial masses [63]. Absolute contraindications include esophageal diseases, recent gastroesophageal surgery, and severe respiratory depression. Informed patient consent should be obtained [64].

Vascular Ultrasound
In the suspicion of cancer therapy-induced PAD, a repeatable and feasible non-invasive method such as duplex ultrasound (DUS) is a first step in the vascular workup both for screening and diagnosis. It includes B-mode echography, pulsed-wave, continuous, color, and power Doppler modalities to detect vascular lesions and quantify their severity through velocity criteria [65]. DUS should be considered also considered for the detection of abdominal aorta aneurysms [66]. In addition, computed tomography angiography (CTA) and/or magnetic resonance angiography (MRA) are indicated for further anatomical characterization of vascular lesions and guidance for optimal revascularization strategy [65].

Cardiac Magnetic Resonance
When TTE is unavailable or non-diagnostic, as in cachectic patients or in patients who have previously undergone left breast or left chest surgery and/or radiotherapy [61], or in case of patients with complex pre-existing heart diseases [61] such as hypertrophic cardiomyopathy, using alternative imaging modalities such as CMR should be considered for serial monitoring of LV size and function.
Although less feasible and more expensive, CMR (a radiation-free technique) has greatly improved accuracy and reproducibility in the estimation of cardiac function structure and function [67,68]. CMR also gives useful data about the existence of previous myocardial infarction scar, diffuse fibrosis, and intracellular or interstitial edema during cancer treatment, often revealing the pathogenesis of cardiotoxicity from the different cancer drug classes and radiation [69,70]. Moreover, new evidence suggests that novel CMR indices may be more sensitive than other imaging modalities regarding anthracyclineinduced damage [71]. In addition, CMR is particularly important when ICI-mediated myocarditis is suspected [72]. Lastly, it is an excellent test for the evaluation of pericardial diseases, cardiac masses, infiltrative (amyloidosis), and storage diseases [73,74]. Of note, CMR protocols for CTRCD evaluation differ in individual cases [75,76].

Cardiac Nuclear Imaging
The historical method of planar imaging multigated acquisition (MUGA) scan is not recommended as a first-line surveillance cardiac imaging modality for cancer patients due to the possibility of using other radiation and accurate techniques, such as cardiac ultrasound and CMR modalities [7,77]. However, fluorodeoxyglucose positron emission tomography (18F-FDG PET) associated with computed tomography or magnetic resonance imaging may be useful to monitor cancer progression and, at the same time, potential drug-induced cardiotoxicity (i.e., ICI-mediated myocarditis when CMR is not available or contraindicated) [61].

Coronary Computed Tomography Angiography and Imaging Stress Tests
Cardiac computed tomography (CCT) plays a major role in any situation in which there is a suspicion of significant CAD or even more suspected obstructive CAD; this would be the more restricted application of CCT, which is coronary computed tomography angiography (CCTA). The clinical diagnostic role of CCT, however, is not limited to that very simple task. CCT can deliver information that is at least as robust as CMR for the anatomy and function of the left/right ventricle, left/right atrium, valves, and pericardium. CCTA has been proposed to detect subclinical CAD as radiation-related coronary damage [78]. In radiotherapy survivors, the accuracy of CCTA and calcium score in the diagnosis of significant CAD is high and demonstrates excellent negative predictive value [79,80]. Notwithstanding, the timing of CCTA for surveillance in asymptomatic cancer survivors following high-dose radiation to the chest is unknown and requires further studies [61].
In patients with suspected angina, stress TTE/CMR (physical or pharmacological depending on the patient's clinical status) is recommended to diagnose the presence and extent of myocardial ischemia and assess the need for therapeutic interventions [61,81].
A list of current guidelines on both cardio-oncology and specific CTR-CVT, used in preparing this review, is displayed in Table 4. Table 4. Employed guidelines on cardio-oncology and on specific CTR-CVT.

Topic
Guidelines Ref.

Conclusions
CVR-CVT may have a strong impact on patients' survival and quality of life, independent of the oncologic prognosis.
In this regard, the combination of serum and imaging markers along with clinical assessment may improve early detection and treatment of cardiotoxicity. It is therefore pivotal to develop integrated multidisciplinary teams in order to provide the most appropriate management for the oncologic patient. In the near future, we do expect a more tailored approach to patient care along with the widespread implementation of digital health tools.